Peripheral arterial disease (PAD) is a highly prevalent condition in the United States, affecting approximately 8-12 million Americans. PAD is largely thought to be a macrovascular disease manifested by atherosclerosis. The contribution of microvascular dysfunction in the end-organ, muscle, to the incidence of symptoms and progression of PAD is uncertain. Similar to vascular disease in the coronary arteries, it is likely that a combination of macrovascular and microvascular dysfunction is involved in the pathophysiology of PAD progression. A more thorough understanding of the pathophysiology of PAD progression and symptom origin is required to provide the basis for new methods of evaluation and novel therapeutic strategies. Aims: Aim-1)To determine in a group of patients with moderate PAD, the relationship between claudication limited exercise tolerance (Peak Walking Time-PWT) and microvascular blood flow. Aim-2)To determine if changes in PWT with exercise rehabilitation correlate with changes in microvascular blood flow. Aim-3) To determine if the vascular health profile, as measured with circulating Endothelial Progenitor Cells (EPCs) and endothelially-derived microparticles (MPs), biomarkers of endothelial health, improves following exercise rehabilitation and correlate with microvascular blood flow. Design & Methods: Subjects with moderate PAD will undergo measurement of treadmill PWT. Continuous Arterial Spin Labeling-Perfusion MRI will be used to measure skeletal muscle calf microvascular blood flow and flow cytometry will be used to characterize the endothelial vascular health profile described above. We anticipate that a supervised exercise rehabilitation program will improve PWT, microvascular blood flow, and the endothelial vascular health profile. PUBLIC HEALTH RELEVANCE: Peripheral arterial disease is a highly prevalent condition in the United States, affecting approximately 8-12 million Americans. Early disability derives from claudication or ischemic muscle pain, inhibiting ambulation. The pathophysiology of this disorder is thought to be of macrovascular origin, however the contribution of the microvasculatrue to this disorder is not well understood and may be important. Improved knowledge of the contribution of the microvasculature to this disorder, and improvement in our ability to monitor, via relatively nonivasive imaging and circulating cellular biomarker assays, the impact of rehabilitation or other therpaeutic interventions, may assist in the treatment of this disorder.